A Phase Ib/II Trial of Selinexor Combined with Lenalidomide and Low Dose Dexamethasone in Patients with Relapsed / Refractory Multiple Myeloma

Introduction - The nuclear export protein exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM). Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates XPO1. Selinexor forces nuclear retention and reactivation of tumor suppressor proteins (TSPs; IkB, p53 and FOXO) and reduction of many proto-oncogenes, including MDM2, MYC and Cyclin D. The combination of lenalidomide/dexamethasone (Rd) is an approved regimen in relapsed/refractory multiple myeloma (RRMM) with an overall response rate (ORR) of 70-76% and a low complete response rate. In combination with selinexor, the anticipated overlapping toxicities are fatigue, thrombocytopenia and neutropenia. We hypothesized that selinexor could be safely combined with Rd and improve efficacy.

Methods - The objective of this phase 1b/2 dose escalation study (NCT02343042) was to determine the tolerability, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) of the combination of selinexor, lenalidomide (len) and dexamethasone (SRd) in RRMM. Patients (pts) with RRMM who received ≥ 1 prior therapy were enrolled. Selinexor was dosed escalated in two regimens once-weekly (QW) or twice weekly (BIW) with both dosing cohorts starting at 60 mg, len 25 mg PO daily and dexamethasone (dex) 20 mg BIW or 40 mg QW.

Results - As of 15-Jul-2017, 18 pts (13 male / 5 female) were enrolled. The median age was 68 years and pts received a median of 1 (range, 1 - 7) prior treatment regimen. Thrombocytopenia was the most common side effect with 4 associated DLTs (2 pts each in the 60 mg BIW and 80 QW cohorts). One additional DLT of grade 3 anorexia was observed in the 60 mg BIW cohort. Common treatment-related grade 1/2 adverse events (AEs) included: nausea (67%), anorexia (44%), fatigue (28%), vomiting (28%), and constipation (28%). Grade 3/4 AEs include: thrombocytopenia (56%), neutropenia (39%), fatigue (11%) and anemia (6%). No DLTs were observed with selinexor 60 mg QW and long-term tolerability was observed. Fifteen pts were evaluable for response, of which 11 pts responded for an ORR of 73%. Among the len naïve pts (n=11), an ORR of 91% was seen, including 3 very good partial responses (VGPR), 7 partial responses (PR, 2 unconfirmed) and 1 unconfirmed minor response (MR). Of the len refractory/relapsed pts (n=4), there was 1 unconfirmed PR, 1 MR, and 2 stable disease (SD). Median PFS was 6.6 months with a median follow up of 4 months. Based on tolerability and anti-MM activity the RP2D of SRd is selinexor 60 mg QW, len 25 mg qd and dex 40 mg QW.

Conclusions - The all oral combination of SRd has significant clinical activity in pts with MM. Importantly, in len naïve pts, the ORR was 91%. No new or unexpected toxicities were observed. The combination has no thrombotic, cardiac, pulmonary, liver or renal toxicity. The main DLT was thrombocytopenia. This phase 1 trial demonstrated that selinexor be can safely combined with Rd in RRMM with high ORR in len naïve pts. These results support the further studies in both newly diagnosed MM as well as in RRMM.